Osteoarthritis is caused by the loss of chondrogenic stem/progenitor cells at the articular surface.

Osteoarthritis (OA), which carries an enormous disease burden across the world, is characterised by irreversible degeneration of articular cartilage (AC), and subsequently of bone. The cellular cause of OA is unknown. Here, using lineage tracing in mice, we show that the BMP-antagonist Gremlin 1 (Grem1) marks a novel chondrogenic stem/progenitor (CSP) cell population in the articular surface that generates joint cartilage and subchondral bone during development and adulthood. Notably, this CSP population is depleted when OA-inducing injury is created in two independent models, and with age. OA is also induced by toxin mediated ablation of Grem1 CSP cells in young mice. Transcriptomic analysis and functional modelling in mice revealed articular surface Grem1 CSP cells are dependent on Foxo1; ablation of Foxo1 in Grem1 cells also led to early OA. This analysis identified FGFR3 signalling as a therapeutic target, and injection of its activator, FGF18, caused proliferation of Grem1 CSP cells (but not hypertrophic AC), increased cartilage thickness, and reduced OA pathology. We propose that OA arises from the loss of CSP cells at the articular surface secondary to an imbalance in stem/progenitor cell homeostasis and present a new stem cell progenitor population as a locus for OA therapy. Overall design: Mice with Grem1-TdT and Lepr-TdT mice were grown to 5-6 weeks of age, and inducted with tamoxifen chow for two weeks. Knee cartileage tissues were processed, sorted, and profiled with single cell transcriptomics